{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T01:23:12Z","timestamp":1792718592148,"version":"4.5.0"},"reference-count":58,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2023,11,1]],"date-time":"2023-11-01T00:00:00Z","timestamp":1698796800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["R01DE016530"],"award-info":[{"award-number":["R01DE016530"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["R01DE020843"],"award-info":[{"award-number":["R01DE020843"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000001","name":"NSF","doi-asserted-by":"publisher","award":["NSF 202649"],"award-info":[{"award-number":["NSF 202649"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,1,13]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Insight into the molecular mechanisms governing the development and maintenance of pluripotency is important for understanding early development and the use of stem cells in regenerative medicine. We demonstrate the selective inhibition of mTORC1 signaling is important for developing the inner cell mass (ICM) and the self-renewal of human embryonic stem cells. S6K suppressed the expression and function of pluripotency-related transcription factors (PTFs) OCT4, SOX2, and KLF4 through phosphorylation and ubiquitin proteasome-mediated protein degradation, indicating that S6K inhibition is required for pluripotency. PTFs inhibited mTOR signaling. The phosphorylation of S6 was decreased in PTF-positive cells of the ICM in embryos. Activation of mTORC1 signaling blocked ICM formation and the selective inhibition of S6K by rapamycin increased the ICM size in mouse blastocysts. Thus, selective inhibition of mTORC1 signaling supports the development and maintenance of pluripotency.<\/jats:p>","DOI":"10.1093\/stmcls\/sxad079","type":"journal-article","created":{"date-parts":[[2023,11,6]],"date-time":"2023-11-06T20:45:26Z","timestamp":1699303526000},"page":"13-28","source":"Crossref","is-referenced-by-count":9,"title":["Selective Inhibition of mTORC1 Signaling Supports the Development and Maintenance of Pluripotency"],"prefix":"10.1093","volume":"42","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4268-1118","authenticated-orcid":false,"given":"Jin Koo","family":"Kim","sequence":"first","affiliation":[{"name":"Division of Oral and Systemic Health Sciences, University of California, Los Angeles School of Dentistry , Los Angeles, CA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis G","family":"Villa-Diaz","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Oakland University , Rochester, MI ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas L","family":"Saunders","sequence":"additional","affiliation":[{"name":"Transgenic Animal Model Core, University of Michigan , Ann Arbor, MI ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruiz P","family":"Saul","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Oakland University , Rochester, MI ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suraj","family":"Timilsina","sequence":"additional","affiliation":[{"name":"Stanford Shared FACS Facility, Stanford University , CA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Biologic and Materials Sciences, University of Michigan School of Dentistry , Ann Arbor, MI ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuji","family":"Mishina","sequence":"additional","affiliation":[{"name":"Department of Biologic and Materials Sciences, University of Michigan School of Dentistry , Ann Arbor, MI ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9062-4981","authenticated-orcid":false,"given":"Paul H","family":"Krebsbach","sequence":"additional","affiliation":[{"name":"Division of Oral and Systemic Health Sciences, University of California, Los Angeles School of Dentistry , Los Angeles, CA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,11,1]]},"reference":[{"key":"2025070408470904100_CIT0001","first-page":"681","article-title":"Current status of pluripotent stem cells: moving the first therapies to the clinic","volume-title":"Nat Rev Drug Discov","author":"Kimbrel","year":"2015"},{"key":"2025070408470904100_CIT0002","first-page":"1","article-title":"Concise review: The evolution of human pluripotent stem cell culture: from feeder cells to synthetic coatings","volume-title":"Stem Cells","author":"Villa-Diaz","year":"2013"},{"key":"2025070408470904100_CIT0003","first-page":"154","article-title":"Establishment in culture of pluripotential cells from mouse embryos","volume-title":"Nature","author":"Evans","year":"1981"},{"key":"2025070408470904100_CIT0004","first-page":"7634","article-title":"Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells","volume-title":"Proc Natl Acad Sci USA","author":"Martin","year":"1981"},{"key":"2025070408470904100_CIT0005","first-page":"1145","article-title":"Embryonic stem cell lines derived from human blastocysts","volume-title":"Science","author":"Thomson","year":"1998"},{"key":"2025070408470904100_CIT0006","first-page":"861","article-title":"Induction of pluripotent stem cells from adult human fibroblasts by defined factors","volume-title":"Cell","author":"Takahashi","year":"2007"},{"key":"2025070408470904100_CIT0007","first-page":"663","article-title":"Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors","volume-title":"Cell","author":"Takahashi","year":"2006"},{"key":"2025070408470904100_CIT0008","first-page":"1917","article-title":"Induced pluripotent stem cell lines derived from human somatic cells","volume-title":"Science","author":"Yu","year":"2007"},{"key":"2025070408470904100_CIT0009","first-page":"274","article-title":"mTOR signaling in growth control and disease","volume-title":"Cell","author":"Laplante","year":"2012"},{"key":"2025070408470904100_CIT0010","first-page":"1193","article-title":"Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients","volume-title":"Science","author":"Kaeberlein","year":"2005"},{"key":"2025070408470904100_CIT0011","first-page":"111","article-title":"Inhibition of mRNA translation extends lifespan in Caenorhabditis elegans","volume-title":"Aging Cell","author":"Pan","year":"2007"},{"key":"2025070408470904100_CIT0012","first-page":"620","article-title":"Genetics: influence of TOR kinase on lifespan in C elegans","volume-title":"Nature","author":"Vellai","year":"2003"},{"key":"2025070408470904100_CIT0013","first-page":"35","article-title":"Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster","volume-title":"Cell Metab","author":"Bjedov","year":"2010"},{"key":"2025070408470904100_CIT0014","first-page":"885","article-title":"Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway","volume-title":"Curr Biol","author":"Kapahi","year":"2004"},{"key":"2025070408470904100_CIT0015","first-page":"149","article-title":"4E-BP extends lifespan upon dietary restriction by enhancing mitochondrial activity in Drosophila","volume-title":"Cell","author":"Zid","year":"2009"},{"key":"2025070408470904100_CIT0016","first-page":"392","article-title":"Rapamycin fed late in life extends lifespan in genetically heterogeneous mice","volume-title":"Nature","author":"Harrison","year":"2009"},{"key":"2025070408470904100_CIT0017","first-page":"140","article-title":"Ribosomal protein S6 kinase 1 signaling regulates mammalian life span","volume-title":"Science","author":"Selman","year":"2009"},{"key":"2025070408470904100_CIT0018","first-page":"2397","article-title":"TSC-mTOR maintains quiescence and function of hematopoietic stem cells by repressing mitochondrial biogenesis and reactive oxygen species","volume-title":"J Exp 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factors","volume-title":"Stem Cells Dev","author":"He","year":"2012"},{"key":"2025070408470904100_CIT0035","first-page":"119","article-title":"Inhibition of mTOR induces a paused pluripotent state","volume-title":"Nature","author":"Bulut-Karslioglu","year":"2016"},{"key":"2025070408470904100_CIT0036","first-page":"236","article-title":"Metabolic Control over mTOR-Dependent Diapause-like State","volume-title":"Dev Cell","author":"Hussein","year":"2020"},{"key":"2025070408470904100_CIT0037","first-page":"908","article-title":"Rapamycin and other longevity-promoting compounds enhance the generation of mouse induced pluripotent stem cells","volume-title":"Aging Cell","author":"Chen","year":"2011"},{"key":"2025070408470904100_CIT0038","first-page":"581","article-title":"Synthetic polymer coatings for long-term growth of human embryonic stem cells","volume-title":"Nat Biotechnol","author":"Villa-Diaz","year":"2010"},{"key":"2025070408470904100_CIT0039","first-page":"1037","article-title":"Fabrication of synthetic polymer coatings and their use in feeder-free culture of human embryonic stem cells","volume-title":"Nat Protoc","author":"Nandivada","year":"2011"},{"key":"2025070408470904100_CIT0040","first-page":"1410","article-title":"Derivation and long-term culture of transgene-free human induced pluripotent stem cells on synthetic substrates","volume-title":"Stem Cells Transl Med","author":"Villa-Diaz","year":"2014"},{"key":"2025070408470904100_CIT0041","first-page":"219","article-title":"Anatomy of a blastocyst: cell behaviors driving cell fate choice and morphogenesis in the early mouse embryo","volume-title":"Genesis","author":"Schrode","year":"2013"},{"key":"2025070408470904100_CIT0042","first-page":"170210","article-title":"The first cell-fate decision of mouse preimplantation embryo development: integrating cell position and polarity","volume-title":"Open Biol","author":"Mihajlovic","year":"2017"},{"key":"2025070408470904100_CIT0043","first-page":"11315","article-title":"Electroporation enables the efficient mRNA delivery into the mouse zygotes and facilitates CRISPR\/Cas9-based genome editing","volume-title":"Sci Rep","author":"Hashimoto","year":"2015"},{"key":"2025070408470904100_CIT0044","first-page":"24731","article-title":"Transcriptional regulation of nanog by OCT4 and SOX2","volume-title":"J Biol Chem","author":"Rodda","year":"2005"},{"key":"2025070408470904100_CIT0045","first-page":"2114","article-title":"KLF4 and PBX1 directly regulate NANOG expression in human embryonic stem cells","volume-title":"Stem Cells","author":"Chan","year":"2009"},{"key":"2025070408470904100_CIT0046","first-page":"797","article-title":"TOS motif-mediated raptor binding regulates 4E-BP1 multisite phosphorylation and function","volume-title":"Curr Biol","author":"Schalm","year":"2003"},{"key":"2025070408470904100_CIT0047","first-page":"398","article-title":"The Hippo signaling pathway components Lats and Yap pattern Tead4 activity to distinguish mouse trophectoderm from inner cell mass","volume-title":"Dev Cell","author":"Nishioka","year":"2009"},{"key":"2025070408470904100_CIT0048","first-page":"125","article-title":"Inequality in function of the right and left ovaries and uterine horns of the mouse","volume-title":"J Reprod Fertil","author":"Wiebold","year":"1987"},{"key":"2025070408470904100_CIT0049","first-page":"85","article-title":"Polytocus focus: Uterine position effect is dependent upon horn size","volume-title":"Int J Dev Neurosci","author":"McLaurin","year":"2015"},{"key":"2025070408470904100_CIT0050","first-page":"1255","article-title":"Staging of gastrulating mouse embryos by morphological landmarks in the dissecting microscope","volume-title":"Development","author":"Downs","year":"1993"},{"key":"2025070408470904100_CIT0051","first-page":"9","article-title":"Mouse and human blastocyst-derived stem cells: vive les differences","volume-title":"Development","author":"Rossant","year":"2015"},{"key":"2025070408470904100_CIT0052","first-page":"617","article-title":"Transient activation of autophagy via Sox2-mediated suppression of mTOR is an important early step in reprogramming to pluripotency","volume-title":"Cell Stem Cell","author":"Wang","year":"2013"},{"key":"2025070408470904100_CIT0053","first-page":"783","article-title":"Regulation of pluripotency and cellular reprogramming by the ubiquitin-proteasome system","volume-title":"Cell Stem Cell","author":"Buckley","year":"2012"},{"key":"2025070408470904100_CIT0054","first-page":"304","article-title":"Increased proteasome activity in human embryonic stem cells is regulated by 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